The long-term objectives of the proposed research are to: illuminate the roles of calcineurin and FRAP/TOR proteins in the nutrient signaling network, illuminate the FRAP-dependent signaling network in glucose-responsive pancreatic islets and insulin-responsive adipocytes and hepatocytes, determine the possible role of this network in type II diabetes, illuminate the ATR-dependent replication checkpoint, determine whether it can be exploited as a means to selectively kill cancer cells lacking p53, illuminate the functions of members of the histone deactetylase (HDAC) family of proteins. The health-relatedness of this research concerns diabetes and cancer. The proposed research will address a new hypothesis concerning the origins of type Il diabetes that unifies the three pathways (arms) that must undergo mis-regulation in order to acquire diabetes. This hypothesis focuses on the single FRAP pathway that can dominantly override these three arms. Diabetes apparently can be induced in humans by modulating the function of human FRAP with rapamycin. Two aspects of this research relate to cancer. Inhibitors of the AIR protein will be sought since AIR inhibition was shown to induce death in cells by causing them to condense their chromatin prematurely, and this route to cell death is amplified in cells engineered to harbor oncogenes or to lack tumor suppressors. AIR inhibitors could be used to determine whether tumors show this same sensitivity. Inhibitors of the individual members of the HDAC family will be identified and used to probe HDAC function. Art HDAC inhibitor has been shown to be effective in reversing an otherwise recalcitrant cancer in a human patient. The compounds that are being sought may illuminate the role of specific HEAC family members in cancer. The design of this research program centers about the use of small molecules to explore biology in a systematic way (chemical genetics). One example is the use of chemical genetic modifier screens, where small molecules are identified that either enhances or suppresses a perturbation of interest (for example, SMIRs suppress the induction of a glucose-starved state by rapamycin, SMIFs suppress the sensitivity of cells to salt stress induced by FK506, and SMITs suppress a chromatin-altered state induced by trichostatin). These small molecules serve as probes of the processes they modify and illuminate the ways in which small molecules might convert diseased states into healthy states.